Several types of tumors and rapidly dividing cells in tissue culture exhibit high rates of sterol synthesis. Suppression of the activity of hydroxymethylglutaryl-CoA reductase (the rate-limiting enzyme in the sterol pathway) decreases the growth and viability of log-phase cells in culture, without affecting quiescent cells. The first goal of the proposed studies is to determine whether Mevinolin and 25-hydroxycholesterol (25-HC), both potent inhibitors of sterol synthesis, can retard the growth of subcutaneous tumors in mice and intracranical tumors in rats. Criteria used to evaluate tumor growth will include tumor weight, cell cycle kinetics of dissociated cells (flow cytometry), 3H-thymidine labelling index and clonogenicity. The second goal will be to elucidate the mechanisms underlying arrest of cell cycling by Mevinolin and 25-HC and to establish whether their effects are restricted to a specific phase of the cell cycly in synchronized C6 glioma cells. Toward this end will attempt to correlate changes in cell cycling with changes in synthesis of cholesterol and products of branches of the sterol pathway (e.g., ubiquinone, dolichol). The effects of Mevinolin and 25-HC on membrane lipid composition and fluidity will also be determined in glioma cells and normal fibroblasts. Finally, we will determine whether changes in the cholesterol pathway normally coincide with the passage of cells through the cell cycle. Synchronous cells will be isolated by centrifugal elutriation and cell cycle-dependent changes in sterol synthesis will be correlated with membrane lipid composition, ubiquinone synthesis, dolichol synthesis, cellular energy charge, glycoprtein synthesis and membrane fluidity. The proposed studies could uncover new approaches to tumor therapy based on selective interference with the sterol pathway. The results will also indicate whether Mevinolin or 25-HC merit further study as chemotherapeutic agents. Delineation of the mechanism and cell cycle specificity of these agents may indicte whether they might be used to potentiate the action of other cell cycle-specific antineoplastic drugs. The extensive basic studies of membrane lipids and sterol synthesis in synchronized C6 glioma cells and other malignant and normal cell lines may identify specific changes that are required for malignant cells to continue to progress through the cell cycle.